Girard T J, MacPhail L A, Likert K M, Novotny W F, Miletich J P, Broze G J
Division of Hematology/Oncology, Jewish Hospital, Washington University Medical Center, St. Louis, MO 63110.
Science. 1990 Jun 15;248(4961):1421-4. doi: 10.1126/science.1972598.
Lipoprotein-associated coagulation inhibitor (LACI) appears to inhibit tissue factor (TF)-induced blood coagulation by forming a quaternary inhibitory complex containing factor Xa, LACI, factor VIIa, and TF. A genetically engineered hybrid protein consisting of the light chain of factor Xa and the first Kunitz-type inhibitor domain of LACI is shown to directly inhibit the activity of the factor VIIa-TF catalytic complex. Unlike inhibition of factor VIIa-TF activity by native LACI, inhibition by the hybrid protein is not dependent on factor Xa. In an assay of TF-induced coagulation, 50% TF inhibition occurs with hybrid protein at 35 nanograms per milliliter, whereas LACI at 2.5 micrograms per milliliter is required for an equivalent effect. gamma-Carboxylation of glutamic acid residues in the factor Xa light chain portion of the hybrid protein is required for inhibitory activity, indicating that the first Kunitz-type domain of LACI alone is not sufficient for inhibition of factor VIIa-TF.
脂蛋白相关凝血抑制剂（LACI）似乎通过形成一种包含因子Xa、LACI、因子VIIa和组织因子（TF）的四级抑制复合物来抑制TF诱导的血液凝固。一种由因子Xa轻链和LACI的第一个Kunitz型抑制剂结构域组成的基因工程杂交蛋白被证明可直接抑制因子VIIa-TF催化复合物的活性。与天然LACI对因子VIIa-TF活性的抑制不同，杂交蛋白的抑制作用不依赖于因子Xa。在TF诱导的凝血测定中，杂交蛋白在每毫升35纳克时可产生50%的TF抑制作用，而产生同等效果则需要每毫升2.5微克的LACI。杂交蛋白因子Xa轻链部分的谷氨酸残基的γ-羧化是抑制活性所必需的，这表明单独的LACI第一个Kunitz型结构域不足以抑制因子VIIa-TF。
